A body’s response that protects from atherosclerosis
Atherosclerosis is a disease in which fatty deposits slowly build up inside arteries, making them narrower and harder over time. This reduces blood flow and can lead to heart attacks, strokes or poor circulation when vital organs don’t get enough oxygen.
“Atherosclerosis is a major cause of death despite fat-lowering therapies, partly because non-fat drivers of vascular injury are poorly defined,” said corresponding author Dr. Yuqing Huo, professor and Danny B. Jones Endowed Chair in Ophthalmology, professor of medicine and molecular and cellular biology, and member of the Cardiovascular Research Institute, all at Baylor. “In the current study, published in the Proceedings of the National Academy of Sciences, we took a closer look at endothelial cells that line the inside of blood vessels and their response to factors that promote atherosclerosis.”
Responding to disturbed flow
Atherosclerotic lesions develop preferentially at arterial regions exposed to disturbed flow (d-flow), which causes DNA damage, genomic stress, endothelial injury and endothelial barrier dysfunction.
“We know that d-flow can reprogram endothelial cell metabolism,” said first author Dr. Qian Ma, postdoctoral associate in ophthalmology working in the Huo lab.
We focused on understanding the effect of d-flow on the cells’ ability to repair DNA damage. Specifically, we investigated how d-flow affected the synthesis of purines, building blocks for new DNA molecules needed to repair DNA.”
Huo, Ma and their colleagues worked with carotid arteries from a mouse model and with living models. They showed that d-flow stimulates the expression of genes involved in the synthesis of new purines in endothelial cells and that this response aligns with endothelial cells engaged in repairing damaged DNA.
Deleting an enzyme involved in purine synthesis called Atic led to endothelial cell death, disruptions in endothelial barrier integrity and accelerated atherosclerosis,” Ma said. “Supplementing purines reverted these effects.”
“Our findings reveal that while d-flow damages endothelial cells, they are not passive bystanders, they attempt to protect themselves by engaging DNA repair pathways that can preserve endothelial barrier function and slow down atherosclerosis progression,” Huo said.
This work suggests that future therapies that strengthen endothelial DNA repair could complement cholesterol-lowering drugs and reduce the risk of atherosclerosis and subsequent heart disease.”
This study also raises concerns about cancer drugs that block the synthesis of new purines, which currently are under investigation. “Our study suggests that these drugs could carry the unintentional side effect of preventing endothelial cells from repairing damaged DNA,” Huo said. “Our findings support careful evaluation of these drugs’ potential to compromise endothelial cell integrity.”
Other contributors to this work include Yongfeng Cai, Dingwei Zhao, Yuan Zhao, Peishan Xu, Tammy Lu, Wendy Zhang, Qiuhua Yang, Yaqi Zhou, Varadarajan Sudhahar, Tohru Fukai and Hanjoong Jo. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Anhui Medical University, Guangzhou Medical University, Rowan-Virtua School of Osteopathic Medicine, Stony Brook University, Augusta University, Emory University and Georgia Institute of Technology.
This work was supported by grants from the American Heart Association (22TPA968801, 23POST1026238) and National Institutes of Health (R01EY030500, R01EY033369, R01EY033737, 1K99HL175106-01A1).
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